In summary, our findings indicated that zebularine and TSA can down-regulate DNMT1, DNMT3a, DNMT3b, class I HDACs (HDACs 1, 2, 3) and class II HDACs (HDACs 4, 5, 6) resulting in reactivation of p21Cip1/Waf1/Sdi1, p27Kip1, p57Kip2, cell growth inhibition and apoptosis induction of colon cancer LS 174T cell line. Here, CDKN1A is linked to malignant colon neoplasm.